We recently demonstrated that the intestinal mucosa is the major site of CD4+ T cell depletion in acute SIV infection Severe depletion of CD4+ T cells occurs rapidly (within days), selectively, and consistently within the gastrointestinal tract following intravenous infection with standard pathogenic molecular clones of SIV No significant changes in single-positive CD4+ T cells can be detected in the blood, peripheral lymph nodes, or spleen of these same animals at these same postinoculation intervals To determine whether this phenomenon occurs following SIV infection by other routes of inoculation, we have since tested six rectally inoculated macaques and found that comparable early CD4+ T cell depletion also occurs following a mucosal route of inoculation Profound and rapid intestinal CD4 depletion occurred within 14 days postinoculation in all six of these animals We have also expanded our analysis to include other mucosal sites (vagina, rectum, lung) a nd h ave found that rapid and profound CD4+ T cell depletion occurs in these sites as well Our data demonstrates that rapid CD4 depletion occurs within days of SIV infection in all mucosal tissues and also that it occurs independently of the site or route of the initial inoculation These results show that SIV infection is predominantly a disease of the mucosal immune system